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2/2: Sickle Cell Disease Treatment with Arginine Therapy (STArT) trial

2/2：精氨酸疗法治疗镰状细胞病 (START) 试验

基本信息

批准号：
10488190
负责人：
Theron C Casper
金额：
$ 55.34万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-20 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10488190
关键词：
Absence of pain sensation Accident and Emergency department Acute Acute Pain Affect African American population Amino Acids Area Arginine Biological Biological Availability Biometry Blood Blood Cells Blood Vessels Cell Adhesion Molecules Cell Density Cells Child Child Care Childhood Clinical Communication Complex Controlled Clinical Trials Data Data Collection Data Coordinating Center Data Set Death Rate Disease Dose Double-Blind Method Down-Regulation Drug Kinetics Electrons Emergency department visit Erythrocytes Event Goals Hemolysis Hemolytic Anemia Hospitalization Hospitals Hour Human Resources Hydration status Individual Inflammatory Inherited Inpatients Intervention Lead Leadership Length of Stay Logistics Maintenance Manuals Mitochondria Monitor Narcotics Nitric Oxide Pain Pathway interactions Patient Care Patients Perfusion Phase Physiology Placebo Control Placebos Plasma Platelet Aggregation Inhibition Preparation Production Protocols documentation Randomized Reperfusion Injury Reporting Research Research Personnel Resolution Safety Schools Sickle Cell Sickle Cell Anemia Specimen Supplementation Syndrome Technical Expertise Testing Therapy trial Time Training Transgenic Mice Universities Utah Vasodilator Agents acute care aged arginase arginine treatment base clinical practice clinical trial analysis clinically relevant data management design double-blind placebo controlled trial efficacious intervention efficacy testing emergency settings experience improved lung injury metabolome mitochondrial dysfunction mortality mouse model neglect new therapeutic target novel therapeutics operation opioid use oxidation pain score pediatric emergency phase III trial pleiotropism primary endpoint product development randomized placebo-controlled clinical trial safety testing standard of care trend vaso-occlusive pain ward

项目摘要

Project Summary/Abstract Vaso-occlusive painful episodes (VOE) in sickle cell disease (SCD) are the leading cause of hospitalizations, emergency room (ED) visits, and missed school, and are associated with an increased mortality rate. There are no current therapies to relieve vaso-occlusion, with interventions limited to hydration and analgesia. Nitric oxide (NO), produced by the 5-electron oxidation of L-arginine, is a potent vasodilator and exerts pleiotropic effects on vascular and circulating blood cells, including the inhibition of platelet aggregation, down-regulation of adhesion molecules, and modulation of ischemia-reperfusion injury, all pathways adversely affected during VOE. We have found that pediatric SCD patients admitted with VOE have depleted plasma L-arginine levels. Additionally, we have now completed a single-center randomized, double-blinded, placebo-controlled trial of arginine therapy in 54 children with VOE requiring hospitalization. We observed a reduction in total opioid use (mg/kg) by 54% and signiﬁcantly lower pain scores at discharge in children who received 5 days IV L-arginine therapy every 8 hours compared to placebo, as well as a clinically relevant trend in reduced length of hospital stay of approximately 17 hours. In pharmacokinetic studies, we found that IV arginine induced a dose-dependent improvement in mitochondrial function in children with SCD hospitalized for pain. We now propose to extend these results to a pivotal phase 3 trial of L-arginine for VOE. We hypothesize that arginine is a safe intervention with narcotic-sparing effects in pediatric SCD patients with VOE that will decrease the time children experience severe pain. Aim 1 of this study will determine the efﬁcacy of IV arginine therapy on the primary endpoint, time-to-crisis resolution, as well as total parenteral opioid use (mg/kg) and pain scores in children with SCD and VOE compared to placebo (Efﬁcacy). Aim 2 will monitor for safety of IV L-arginine (Safety). Aim 3 will characterize alterations in the arginine metabolome and mitochondrial function in children with SCD and VOE, and evaluate how it is impacted by IV arginine therapy (Exploratory). This proposal will provide essential data for product development and FDA regulatory approval for use of arginine in SCD. Acute care of patients with SCD and pain in the ED is a neglected area of research. The results of this study may ultimately lead to change in clinical practice for children with SCD in both the ED and inpatient hospital wards. ED-based studies and novel therapies that target mechanisms of vaso-occlusion and pain are needed in SCD.

项目总结/摘要镰状细胞病（SCD）中的血管闭塞性疼痛发作（VOE）是住院的主要原因，急诊室（艾德）就诊和缺课，并与死亡率增加有关。有目前没有缓解血管闭塞的治疗方法，干预措施仅限于水合作用和镇痛。一氧化氮 (NO)由L-精氨酸的5-电子氧化产生，是一种有效的血管扩张剂，血管和循环血细胞，包括抑制血小板聚集，下调粘附分子和缺血-再灌注损伤的调节，所有途径在VOE期间受到不利影响。我们有发现患有VOE的儿童SCD患者的血浆L-精氨酸水平已耗尽。另外我们现在已经完成了一项单中心随机、双盲、安慰剂对照的精氨酸治疗试验， 54名VOE儿童需要住院治疗。我们观察到阿片类药物的总使用量（mg/kg）减少了54%，每8小时接受5天IV L-精氨酸治疗的儿童出院时疼痛评分显著降低与安慰剂相比， 17个小时在药代动力学研究中，我们发现静脉注射精氨酸可诱导剂量依赖性的改善，因疼痛住院的SCD儿童的线粒体功能。我们现在建议将这些结果推广到 L-精氨酸治疗VOE的关键III期试验。我们假设精氨酸是一种安全的干预措施，在患有VOE的儿童SCD患者中的作用，将减少儿童经历剧烈疼痛的时间。目标1 本研究将确定静脉精氨酸治疗对主要终点（至危机解决时间）的有效性，以及与安慰剂相比，SCD和VOE儿童的总胃肠外阿片类药物使用量（mg/kg）和疼痛评分 (Ef办公室）。目标2将监测IV L-精氨酸的安全性（安全性）。目标3将描述精氨酸代谢组和线粒体功能在SCD和VOE儿童，并评估它是如何影响静脉注射精氨酸治疗（探索性）。该提案将为产品开发和FDA提供必要的数据监管机构批准精氨酸用于SCD。在艾德，SCD和疼痛患者的急性护理是一个被忽视的研究领域。这项研究的结果可能最终导致SCD儿童临床实践的改变在艾德和住院部都有。以ED为基础的研究和新疗法，血管闭塞和疼痛是SCD所必需的。